DESCRIPTION (Applicant's Abstract): The following revised competitive application reflects the PI's programmatic attempt to examine the contribution of serotonergic factors to the mechanism underlying differences in antidepressant response (ADRs) in depressed patients. The proposal has been revised in response to the last review, and presents a direct extension of the groundwork laid, and the findings resulting from the PI's initial funding, suggesting that differences in 2 serotonin recognition sites, the serotonin transporter (5-HTT), and the 5-HT 1A receptor, both contribute to the variance in antidepressant (AD) responses. The initial findings from the PI's laboratory suggest that an adequate shift in the apparent affinity of the 5-HTT, and subsequent functional downregulation of the 5-HT 1A receptor, are necessary for an antidepressant response to nortripyline to occur. The present proposal will extend these findings in 2 important ways, first examining the extension of their applicability to treatment with an SSRI, and also to therapeutically exploit these novel principles to test a new pharmacologic strategy i.e., whether blockade of the 5-HT 1A receptors will result in a rapid antidepressant treatment response by functionally downregulating them prior to the time lag for their desentitzation. This proposal will also employ new strategies for determining some of the potential mechanisms underlying differences in antidepressant responses by examining whether genetic differences may contribute to different 5-HTT and 5-HT 1A receptor actions in depressed patients, again as an extension of our data to date. This project will explore new data from our laboratories related to 2 new polymorphisms found in the 5-HTT DNA this year, one in the promoter region identified by SSCP, as well as a new RFLP which appears to be more common in the homozygous case in depressed patients, and extend these techniques to study of the 5-HT 1A receptor in this project.